Friday, September 27, 2013

The Extraordinary Human Epigenome

We learned a lot about genes and gene expression in the second half of the 20th century. We learned that genes are transcribed and we have a pretty good understanding of how transcription initiation complexes are formed and how transcription works.

We learned how transcription is regulated through promoter strength, activators, and repressors. Activators and repressors bind to DNA and those binding sites can lie at some distance from the promoter leading to formation of loops of DNA that bring the regulatory proteins into contact with the transcription complex. Much of our basic understanding of this process was derived from detailed studies of bacteriophage and bacterial genes.

THEME:TranscriptionLater on we learned that eukaryotic genes expression was very similar and regulation also required repressors and activators. We discovered that gene expression was associated with chromatin remodeling that opened up regions of the chromosome that were tightly bound to histones in 30nm or higher order structures.

Building on studies in prokaryotes, we learned about temporal gene regulation and differentiation. Much of the work was done in model organisms like Drosophila, yeast, C. elegans, and various mammalian cells in culture.

By the end of the century I was pretty confident that what I wrote in my textbook was a fair representation of the fundamental concepts in gene expression and regulation.

Turns out I was wrong as I just discovered this morning when I read the opening paragraph of a review by Rivera and Ren (2013). Here's what they say ...

More than a decade has passed since the human genome was completely sequenced, but how genomic information directs spatial- and temporal-specific gene expression programs remains to be elucidated (Lander, 2011). The answer to this question is not only essential for understanding the mechanisms of human development, but also key to studying the phenotypic variations among human populations and the etiology of many human diseases. However, a major challenge remains: each of the more than 200 different cell types in the human body contains an identical copy of the genome but expresses a distinct set of genes. How does a genome guide a limited set of genes to be expressed at different levels in distinct cell types?

Wow! The textbooks need to be rewritten! We didn't learn anything in the last century!

It took me the whole first paragraph of this paper to realize that the rest of it was probably going to be worthless unless you were interested in technical details about the field. That's because I'm not as smart as Dan Graur. He only read the title, "Mapping Human Epigenomes" and the abstract before concluding that the authors were speaking in newspeak1 [A “Leading Edge Review” Reminds Me of Orwell (and #ENCODE)].

The Rivera and Ren paper is a "Leading Edge" review in the prestigious journal Cell. It covers all the techniques used to study methylation, histone modification and binding, transcription factor binding, and nucleosome positioning at the genome level. According to the authors, people like me were fooled by studies on individual genes, purified factors, and in vitro binding assays. That didn't really tell us what was going on.

Apparently, the most effective way of learning about the regulation of gene expression in humans is to analyze the entire genome all at once and read off the data from microarrays and computer monitors. (After shoving it through a bunch of code.)

Overwhelming evidence now indicates that the epigenome serves to instruct the unique gene expression program in each cell type together with its genome. The word "epigenetics," coined half a century ago by combining "epigenesis" and "genetics," describes the mechanisms of cell fate commitment and lineage specification during animal development (Holliday, 1990; Waddington, 1959). Today, the "epigenome" is generally used to describe the global, comprehensive view of sequence-independent processes that modulate gene expression patterns in a cell and has been liberally applied in reference to the collection of DNA methylation state and covalent modification of histone proteins along the genome (Bernstein et al., 2007; Bonasio et al., 2010). The epigenome can differ from cell type to cell type, and in each cell it regulates gene expression in a number of ways—by organizing the nuclear architecture of the chromosomes, restricting or facilitating transcription factor access to DNA, and preserving a memory of past transcriptional activities. Thus, the epigenome represents a second dimension of the genomic sequence and is pivotal for maintaining cell-typespecific gene expression patterns.

Not long ago, there were many points of trepidation about the value and utility of mapping epigenomes in human cells (Madhani et al., 2008). At the time, it was suggested that histone modifications simply reflect activities of transcription factors (TFs), so cataloging their patterns would offer little new information. However, some investigators believed in the value of epigenome maps and advocated for concerted efforts to produce such resources (Feinberg, 2007; Henikoff et al., 2008; Jones and Martienssen, 2005). The last five years have shown that epigenome maps can greatly facilitate the identification of potential functional sequences and thereby annotation of the human genome. Now, we appreciate the utility of epigenomic maps in the delineation of thousands of lincRNA genes and hundreds of thousands of cis-regulatory elements (ENCODE Project Consortium et al., 2012; Ernst et al., 2011; Guttman et al., 2009; Heintzman et al., 2009; Xie et al., 2013b; Zhu et al., 2013), all of which were obtained without prior knowledge of cell-type-specific master transcriptional regulators. Interestingly, bioinformatic analysis of tissue-specific cis-regulatory elements has actually uncovered novel TFs regulating specific cellular states.

So, what are all these new discoveries that now elucidate what was previously unknown; namely, "how genomic information directs spatial- and temporal-specific gene expression programs"?

This is a very long review full of technical details so let's skip right to the conclusions.

Six decades ago, Watson and Crick put forward a model of DNA double helix structure to elucidate how genetic information is faithfully copied and propagated during cell division (Watson and Crick, 1953). Several years later, Crick famously proposed the "central dogma" to describe how information in the DNA sequence is relayed to other biomolecules such as RNA and proteins to sustain a cell’s biological activities (Crick, 1970). Now, with the human genome completely mapped, we face the daunting
task to decipher the information contained in this genetic blueprint. Twelve years ago, when the human genome was first sequenced, only 1.5% of the genome could be annotated as protein coding, whereas the rest of the genome was thought to be mostly "junk" (Lander et al., 2001; Venter et al., 2001). Now, with the help of many epigenome maps, nearly half of the genome is predicted to carry specific biochemical activities and potential regulatory functions (ENCODE Project Consortium, et al., 2012). It is conceivable that in the near future the human genome will be completely annotated, with the catalog of transcription units and their transcriptional regulatory sequences fully mapped.

I hope they hurry up. Not only do I have to re-write my description of the Central Dogma2 but I'm going to have to re-write everything I thought I knew about regulation of gene expression and the organization of information in the human genome. That's going to take time so I hope the epigeneticists will publish lots more whole genome studies in the near future so I can understand the new model of gene expression.

Keep in mind that this paper was published in Cell where it was rigorously reviewed by the leading experts in the field. It must be right.

6 comments
:

Twelve years ago, when the human genome was first sequenced, only 1.5% of the genome could be annotated as protein coding, whereas the rest of the genome was thought to be mostly "junk" (Lander et al., 2001; Venter et al., 2001). Now, with the help of many epigenome maps, nearly half of the genome is predicted to carry specific biochemical activities and potential regulatory functions (ENCODE Project Consortium, et al., 2012)

It's very unfortunate this was written, especially given what has gone on over the last year.

Maybe someone here can offer an explanation on the problem of "missing heritability," aka: missing genetic variance, of complex traits (e.g., human disease) that articles such this one in Cell seem to be addressing? Is it a lack of understanding of genome architecture, the role of epigenetics, etc.?

Surely epistasis plays a role, but missing heritability is probably not any one thing.This piece presents a wide range of opinion on the issue of missing heritability from some top researchers in the field of human genetics.

The authors write: "Twelve years ago, when the human genome was first sequenced, only 1.5% of the genome could be annotated as protein coding, whereas the rest of the genome was thought to be mostly "junk" (Lander et al., 2001; Venter et al., 2001). "

Hey! These geniuses wrote that non-coding DNA was thought to be mostly junk! A year ago they were saying scientists believed non-coding DNA was equal to junk!

That's progress! Another 45 years or so and they'll be writing accurate things in Cell and Nature.

Laurence A. Moran

Larry Moran is a Professor Emeritus in the Department of Biochemistry at the University of Toronto. You can contact him by looking up his email address on the University of Toronto website.

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The Sandwalk is the path behind the home of Charles Darwin where he used to walk every day, thinking about science. You can see the path in the woods in the upper left-hand corner of this image.

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Quotations

The old argument of design in nature, as given by Paley, which formerly seemed to me to be so conclusive, fails, now that the law of natural selection has been discovered. We can no longer argue that, for instance, the beautiful hinge of a bivalve shell must have been made by an intelligent being, like the hinge of a door by man. There seems to be no more design in the variability of organic beings and in the action of natural selection, than in the course which the wind blows.Charles Darwin (c1880)Although I am fully convinced of the truth of the views given in this volume, I by no means expect to convince experienced naturalists whose minds are stocked with a multitude of facts all viewed, during a long course of years, from a point of view directly opposite to mine. It is so easy to hide our ignorance under such expressions as "plan of creation," "unity of design," etc., and to think that we give an explanation when we only restate a fact. Any one whose disposition leads him to attach more weight to unexplained difficulties than to the explanation of a certain number of facts will certainly reject the theory.

Charles Darwin (1859)Science reveals where religion conceals. Where religion purports to explain, it actually resorts to tautology. To assert that "God did it" is no more than an admission of ignorance dressed deceitfully as an explanation...

Quotations

The world is not inhabited exclusively by fools, and when a subject arouses intense interest, as this one has, something other than semantics is usually at stake.
Stephen Jay Gould (1982)
I have championed contingency, and will continue to do so, because its large realm and legitimate claims have been so poorly attended by evolutionary scientists who cannot discern the beat of this different drummer while their brains and ears remain tuned to only the sounds of general theory.
Stephen Jay Gould (2002) p.1339
The essence of Darwinism lies in its claim that natural selection creates the fit. Variation is ubiquitous and random in direction. It supplies raw material only. Natural selection directs the course of evolutionary change.
Stephen Jay Gould (1977)
Rudyard Kipling asked how the leopard got its spots, the rhino its wrinkled skin. He called his answers "just-so stories." When evolutionists try to explain form and behavior, they also tell just-so stories—and the agent is natural selection. Virtuosity in invention replaces testability as the criterion for acceptance.
Stephen Jay Gould (1980)
Since 'change of gene frequencies in populations' is the 'official' definition of evolution, randomness has transgressed Darwin's border and asserted itself as an agent of evolutionary change.
Stephen Jay Gould (1983) p.335
The first commandment for all versions of NOMA might be summarized by stating: "Thou shalt not mix the magisteria by claiming that God directly ordains important events in the history of nature by special interference knowable only through revelation and not accessible to science." In common parlance, we refer to such special interference as "miracle"—operationally defined as a unique and temporary suspension of natural law to reorder the facts of nature by divine fiat.
Stephen Jay Gould (1999) p.84

Quotations

My own view is that conclusions about the evolution of human behavior should be based on research at least as rigorous as that used in studying nonhuman animals. And if you read the animal behavior journals, you'll see that this requirement sets the bar pretty high, so that many assertions about evolutionary psychology sink without a trace.

Jerry Coyne
Why Evolution Is TrueI once made the remark that two things disappeared in 1990: one was communism, the other was biochemistry and that only one of them should be allowed to come back.

Sydney Brenner
TIBS Dec. 2000
It is naïve to think that if a species' environment changes the species must adapt or else become extinct.... Just as a changed environment need not set in motion selection for new adaptations, new adaptations may evolve in an unchanging environment if new mutations arise that are superior to any pre-existing variations

Douglas Futuyma
One of the most frightening things in the Western world, and in this country in particular, is the number of people who believe in things that are scientifically false. If someone tells me that the earth is less than 10,000 years old, in my opinion he should see a psychiatrist.

Francis Crick
There will be no difficulty in computers being adapted to biology. There will be luddites. But they will be buried.

Sydney Brenner
An atheist before Darwin could have said, following Hume: 'I have no explanation for complex biological design. All I know is that God isn't a good explanation, so we must wait and hope that somebody comes up with a better one.' I can't help feeling that such a position, though logically sound, would have left one feeling pretty unsatisfied, and that although atheism might have been logically tenable before Darwin, Darwin made it possible to be an intellectually fulfilled atheist

Richard Dawkins
Another curious aspect of the theory of evolution is that everybody thinks he understand it. I mean philosophers, social scientists, and so on. While in fact very few people understand it, actually as it stands, even as it stood when Darwin expressed it, and even less as we now may be able to understand it in biology.

Jacques Monod
The false view of evolution as a process of global optimizing has been applied literally by engineers who, taken in by a mistaken metaphor, have attempted to find globally optimal solutions to design problems by writing programs that model evolution by natural selection.